4. The role of the let-7 family of microRNAs and its targets in tumor progression.

It is becoming increasingly evident that micro (mi)RNAs play an important role in oncogenesis by regulating genes that are involved in transformation (1,2). Since there are approximately 25-30,000 genes in the human genome, but only over 400 miRNAs, there may be miRNA families that govern entire gene expression programs, presumably by regulating a distinct pattern of differentiation. However, a master regulatory function for an miRNA family in carcinogenesis has yet to be described. The Peter lab recently described that CD95 Type I and Type II cells are part of two genetically different superclusters (SC) among the 60 cell lines of the drug screening panel of the National Cancer Institute (NCI60): SC1 cells express an epithelial gene signature, while SC2 cells express a mesenchymal gene profile, suggesting that Type I/SC1 and Type II/SC2 cells represent advanced and less advanced tumor cells, respectively (3). By performing a microRNA gene array analysis to find differences between Type I and Type II, they identified the let-7 family of miRNAs as the best marker genes for Type II/SC2 cells (4). The Peter group identified the early embryonic gene HMGA2 as a direct target for let-7 (4,5). In collaboration with Dr. Ernst Lengyel it was then shown that ovarian cancer patients with high HMGA2 and low let-7 expression have a more adverse prognosis of survival than patients that express low HMGA2/high let-7 in their cancer (4). These data suggest that introducing let-7 into cancer cells should suppress HMGA2 and make cancer less aggressive. Recently, the Peter group has identified a group of 12 let-7 regulated oncofetal genes (LOGs) using an unbiased genome-wide approach (5). The LOGs include HMGA2 and IMP-1 (5). Eight of the 12 LOGs are known to be relevant for cancer progression and could therefore be valid targets for cancer therapy

miRNAs have been demonstrated to regulate and maintain differentiation processes. Let-7 is part of a family of miRNAs that are not expressed in early embryos but are induced at later stages of development and remain upregulated in the adult organism in order to suppress expression of embryonic genes. Starting late during embryonic development, let-7 suppresses expression of embryonic genes (LOGs) (step I in Figure). In the adult organism, a high level of let-7 ensures permanent repression of these genes in most terminally differentiated tissues (step II in Figure). Early during cancer development, and this stage could be different for each type of cancer, let-7 expression is lost and LOGs are upregulated giving cancer cells many of the properties of embryonic cells (step III in Figure) (6). The Peter lab is currently engaged in a comprehensive analyses of these embryonic genes that are controlled by let-7 and that could be upregulated during tumor progression.

References

1.	Park, S.-M. and Peter, M.E. (2008) microRNAs and death receptors. Cytokine Growth Factor Rev, in press.
2.	Schickel, R., Boyerinas, B., Park, S.-M. and Peter, M.E. (2008) MicroRNAs: keyplayers in the immune system, differentiation, tumorigenesis and cell death. Oncogene, in press.
3.	Algeciras-Schimnich, A., Pietras, E., Barnhart, B.C., Legembre, P., Vijayan, S., Holbeck, S.L. and Peter, M.E. (2003) Two CD95 tumor classes with different sensitivites to antitumor drugs. Proc. Natl. Acad. Sci. USA, 100, 11445-11450.
4.	Shell, S., Park, S.-M., Radjabi, A.R., Schickel, R., Kistner, E.O., Jewell, D.A., Feig, C., Lengyel, E. and Peter, M.E. (2007) Let-7 expression defines two differentiation stages of cancer. Proc. Natl. Acad. Sci. USA, 104:11400-11405. News coverage in: Arcor, Apria, EARTHtimes, EurekAlert, Genetic Engineering & Biotechnology News, Imedinews, Health and Science Roundup, News-Medical.Net, newswise, Omniomix, Physorg, ScienceDaily, scientist LIVE, Healthcare Industry Today, United Press International, BrightSurf, ZZN Magazine, innovations report, NewsVantage, Ustinet News, Political Gateway, Breitbart, IW Industry Watch, DentalPlans, Nerve of India, NIH/NIGMS, Scientific Frontline Communication Center, Inbox Robot, Good News Daily, Biocompare, Siftcom, WebIndia123, Netrition Health News, Medical News Today, Lung Cancer Alliance, Rocky Mountain Cancer Centers, MaxHealth, ArcaMax Publishing, Medilexicon, Bioresearch Online, Iconocast, Cancer Research Online, The Science Coalition, Medical Student Romania, Daily India, Interest! Alert, EARTHtimes.org, Topix, Moraga, The Ovarian Cancer Website, NanoGallery, DiscoveR8, Isis, Annals of Oncology, RedOrbit, HealthTitle and many others.
5.	Boyerinas, B, Park, S.M., Shomron, N., Hedegaard, M.M, Vinther, J., Andersen, J.S., Feig, C., Xu, X., Burge, C. and Peter, M.E. (2008) Identification of let-7-regulated oncofetal genes. Cancer Res. (Priority Report), 68, 2587-2591.
6.	Park, S.M., Shell, S., Radjabi, A.R., Schickel, R., Feig, C., Boyerinas, B., Dinulescu, D.M., Lengyel, E. and Peter, M.E. (2007) Let-7 prevents early cancer progression by suppressing expression of the embryonic gene HMGA2. Cell Cycle, 6, 2585-2590.